Robust estimates of hypoxic extent (both area and volume) are important for assessing the impacts of low dissolved oxygen on aquatic ecosystems at large spatial scales. Such estimates are also important for calibrating models linking hypoxia to causal factors, such as nutrient loading and stratification, and for informing management decisions. In this study, we develop a rigorous geostatistical modeling framework to estimate the hypoxic extent in the northern Gulf of Mexico from data collected during midsummer, quasi-synoptic monitoring cruises (1985–2011). Instead of a traditional interpolation-based approach, we use a simulation-based approach that yields more robust extent estimates and quantified uncertainty. The modeling framework also makes use of covariate information (i.e., trend variables such as depth and spatial position), to reduce estimation uncertainty. Furthermore, adjustments are made to account for observational bias resulting from the use of different sampling instruments in different years. Our results suggest an increasing trend in hypoxic layer thickness (p = 0.05) from 1985 to 2011, but less than significant increases in volume (p = 0.12) and area (p = 0.42). The uncertainties in the extent estimates vary with sampling network coverage and instrument type, and generally decrease over the study period.